Scientists at Stanford University’s School of Medicine have created nanoparticles that are able to precisely highlight brain tumors. Because the nanoparticles can be imaged in three different ways, they can be used to delineate the boundaries of tumors before and during brain surgery to ease the complete removal of tumors. The scientists have already used the nanoparticles to remove brain tumors from mice with unprecedented accuracy and hope the technique could be used on humans in the future.

“With brain tumors, surgeons don’t have the luxury of removing large amounts of surrounding normal brain tissue to be sure no cancer cells are left,” said Sam Gambhir, MD, PhD, and chair of radiology and director of the Molecular Imaging Program at Stanford. “You clearly have to leave as much of the healthy brain intact as you possibly can.”

However, removing the entire tumor while sparing normal brain tissue is nigh on impossible for even the most skillful surgeons. This is particularly true for glioblastomas, the most aggressive form of brain tumor that features rough-edges and tiny, fingerlike projections that commonly follow the paths of blood vessels and nerve tracts to infiltrate healthy tissue.

Miniscule tumor patches, called micrometastases, which are caused by the migration and replication of cells from the primary tumor, can dot otherwise healthy nearby tissue and be invisible to a surgeon’s naked eye before sprouting into new tumors.

The nanoparticles engineered in Gambhir’s lab are essentially miniscule gold balls measuring less than five-millionths of an inch in diameter – roughly one-sixtieth the diameter of a human red blood cell - that are coated with imaging reagents.

“We hypothesized that these particles, injected intravenously, would preferentially home in on tumors but not healthy brain tissue,” said Gambhir, who is also a member of the Stanford Cancer Institute. “The tiny blood vessels that feed a brain tumor are leaky, so we hoped that the spheres would bleed out of these vessels and lodge in nearby tumor material.”

Triple threat imaging

The surface coatings applied to the nanoparticles render them visible to three different imaging techniques, the first being magnetic resonance imaging (MRI). Although MRI's are already used to indicate the location of a tumor pre-operatively, they can’t provide a perfect image of an aggressively growing tumor at the time of an operation.

The second is photoacoustic imaging involves exposing the nanoparticles to pulses of light, which is absorbed by the gold cores, resulting in the particles heating up slightly and producing detectable ultrasound signals that allow a three-dimensional image of the tumor to be computed. The scientists say that this method can be useful in guiding the removal of the bulk of a tumor during surgery because it has high depth penetration and is highly sensitive to the presence of the gold particles.

The third method is called Raman imaging, which is also being used in the SpectroPen that aims to help surgeons define the boundaries of a tumor in real-time during surgery. In this case, the coatings of the gold nanoparticles amplify the almost undetectable Raman signals given off by certain materials so they can be captured by a special microscope.

Put to the test

After demonstrating that the gold nanoparticles specifically targeted only tumor tissue, the team implanted several different types of human glioblastoma cells deep into the brains of laboratory mice. They then injected the coated gold nanoparticles into the mice’s tail veins and were able to visualize the tumors that the glioblastoma cells had spawned with all three imaging techniques.

While neither MRI nor photoacoustic imaging alone could distinguish healthy tissue from cancerous tissue at a sufficiently minute level to identify every last bit of a tumor, MRI scans provided a good image of the general shapes and location of the tumor pre-operatively, while the photoacoustic imaging provided accurate, real-time visualization of the tumors’ edges during an operation.

After clearing the bulk of the mouse’s tumor using these imaging techniques, the highly-sensitive Raman imaging was then used to flag residual micrometastases and tiny fingerlike projections remaining in adjacent healthy tissue that had been missed by visual inspection. As the study found that the Raman signals only emanated from tumor-ensconced nanoparticles, it was possible to remove these dangerous remnants.

“Now we can learn the tumor’s extent before we go into the operating room, be guided with molecular precision during the excision procedure itself and then immediately afterward be able to ‘see’ once-invisible residual tumor material and take that out, too,” said Gambhir.

Gambhir suggests that the nanoparticles' tumor specificity, combined with their ability to heat up on photoacoustic stimulation, might give them the potential to be used to selectively destroy tumors. He added that the precision in highlighting tumors might also be used on other tumor types.

The team’s study is published online in Nature Medicine.